Plasma phospholipids transfer protein (PLTP) is a member of the lipid transfer/lipopolysaccharide binding protein gene family. PLTP is involved in the metabolism of high density lipoprotein (HDL) and apolipoprotein B (apoB)-containing lipoproteins. PLTP is an independent risk factor for coronary artery disease. In mouse models, it has been demonstrated that PLTP deficiency reduces atherosclerosis while its overexpression shows the opposite effect. Therefore, PLTP is considered a promising target for pharmacological interventions on atherosclerosis. However, this possibility is hampered by the fact that the substance's atherogenic mechanism is not completely understood. PLTP is a protein with multiple functions and expressed in various tissues. In order to unravel the complex mechanisms involved, we will use the transgenic and knockout mouse models generated in my and other laboratories, to test our general hypothesis that PLTP has proatherogenic properties. The Specific Aims are: 1) to evaluate the hypothesis that PLTP overexpression and PLTP deficiency represent two distinct states in HDL metabolism and function; 2) to investigate the effect of tissue-specific PLTP overexpression on lipoprotein metabolism and atherosclerosis; and 3) to determine the effect of tissue-specific PLTP deficiency on lipoprotein metabolism and atherosclerosis. This project will provide new information on the relationship between PLTP activity and lipoprotein metabolism, between PLTP activity and atherosclerosis, and will provide biochemical basis for further evaluation of PLTP as a therapeutic target. [unreadable] [unreadable] [unreadable]